Immunosuppression and Rheumatic Disease Flashcards
Give 4 examples of diseases that rheumatologists manage
- Inflammatory arthritis, i.e. rheumatoid arthritis
- Systemic lupud erythematosus
- Systemic vasculitis
What kind of disease is rheumatoid arthritis?
An autoimmune multi-system disease
How common is rheumatoid arthritis?
Fairly common - 1% of UK population
Where is RA initially localised to?
The synovium
What is the synovium?
The tissue covering joints and lining articular surfaces
What happens to the synovium in RA?
There is inflammatory change and proliferation of the synvoium, leading to dissolution of cartilage and bone
What causes RA?
An imbalance between pro-inflammatory and anti-inflammatory cytokines
Give 3 pro-inflammatory cytokines
- IL-1
- IL-6
- TNF-alpha
Give 2 anti-inflammatory cytokines?
- IL-4
- TGF-beta
Other than cytokines, what molecules are involved in the pathogenesis of RA?
- T cells
- B cells
- Macrophages
- Rheumatoid factor
- Metalloproteinases
- Neuropeptides
What kind of diagnosis is RA?
Clinical diagnosis
What are the diagnostic criteria for RA?
- Morning stiffness for >1 hour
- Arthritis of 3 or more joints
- Symmetrical arthritis
- Rheumatoid arthritis
- Rheumatoid arthritis
- Serum rheumatoid factor
- X-ray changes
Why are we moving away from rheumatic nodules, serum rheumatoid factor, and x-ray changes as diagnostic criteria for RA?
We want to try and treat earlier, and these are later changes
What are the treatment goals in RA?
- Symptomatic relief
- Prevention of joint destruction
What is the treatment strategy in RA?
- Early use of disease-modifying drugs
- Use of adequate doses
- Use of combinations of drugs
- Avoidance of use of long-term corticosteroids
When should disease modifying drugs be used in RA?
Start on the day of diagnosis
What is meant by ‘adequate doses’ in RA treatment?
Doses that are adequate in achieving good disease control - aim for remission
Why should you avoid the use of long-term corticosteroids in RA treatment?
Steroids have lots of side effects/complications
What systems of the body can lupus affect?
- Central and peripheral nervous system, e.g. seizures, headaches
- Heart and lungs, e.g. pericarditis, pneumonitis
- Kidneys, e.g. oedema, hypertension
- Reproductive system, e.g. miscarriages, menstrual cycle irregularities
- Blood, e.g. anaemia, thrombocytopenia
- Eyes and mucous membranes, e.g. ulcers in eyes, nose, mouth, or vagina
- Gastrointestinal, e.g. nausea, vomiting
- Musculoskeletal, e.g. extreme fatigue, myalgia
- Skin, e.g. butterfly rash, vasculitis
What organs are affected in vasculitis?
- Lungs
- Skin
What are the treatment goals in SLE and vasculitis?
- Symptomatic relief
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and by drugs
Give 5 examples of immunosuppressant drugs
- Corticosteroids
- Azathioprine
- Ciclosporin
- Tacrolimus
- Mycophenolate mofetil
What is the mechanism of action of corticosteroids?
- Prevent interleukin 1 and 6 (IL-1 and IL-6) production by macrophages
- Inhibits all stages of T cell activation
Give 5 disease-modifying anti-rheumatic drugs (DMARD)
- Methotrexate
- Sulphasalazine
- Anti-TNF agents
- Rituixmab
- Cyclophosphamide
Broadly, what is the advantage of DMARDs over immunosuppressants?
Tend to have a more focused action
How long do DMARDs take to have an effect?
Cyclophosphamide takes about 10 days to have an effect, whereas the others take 4-6 weeks
What are the clinical uses of azathioprine?
- Used as a maintenance therapy in SLE and vasculitis
- RA, although weak evidence
- Inflammatory bowel disease
- Atopic dermatitis
- Bullous skin disease
- Many other uses as a steroid sparing drug
What is meant by a steroid sparing drug?
Allows you to drop steroids early, so you’re not exposed to the side effects of steroids
How is azathioprine metabolised?
- Azathioprine is metabolised to 6-MP
- 6-MP is converted either to;
- 6-MeMP by action of thiopurine methyltransferase (TPMT)
- TIMP
- 6-TI inactive
- TIMP is then converted to;
- 6-MeMPN by action of TPMT
- 6-TGN
What does 6-MeMPN do?
Inhibits de novo purine synthesis
What does 6-TGN do?
Incorporates into DNA
What is the clinical relevance of TPMT?
The TPMT gene is highly polymorphic, and so individuals vary markedly in TPMT activity. When there is low or absent levels of TMPT, there is a risk of myelosuppression, therefore TMPT activity must be tested before prescribing
What are the adverse effects of azathioprine?
- Bone marrow suppression
- Increased risk of malignancy
- Increased risk of infection
- Hepatitis
What should be done due to the risk of bone marrow suppression with azathioprine treatment?
Monitor FBC
Who is especially at risk of malignancy due to azathioprine treatment?
Transplant patients
What should be done due to the increased risk of hepatitis with azathioprine treatment?
Monitor LFTs
Give two examples of calcineurin inhibitors
- Ciclosporin
- Tacrolimus
Where are calcineurin inhibitors used?
- Transplantation
- Atopic dermatitis
- Psoriasis
Why are calcineurin inhibitors not often used in rheumatology?
Due to renal toxicity
What must be done due to the risk of renal toxicity with the use of calcineurin inhibitors?
Check BP and eGFR regularly
Why are multiple drug interatctions possible with calcineurin inhibitors?
Because its action involves the cytochrome P450
Give 4 examples of CYP P450 inducers
- Rifampicin
- Carbamazepine
- Phenytoin
- Omeprazole
Give 5 examples of CYP P450 inducers
- Ciprofloxacin
- Many anti-fungals
- Fluoxetine
- Paroxetine
- HIV anti-virals
What is the mechanism of action of the calcineurin inhibitors?
- They are active against helper T-cells, preventing the production of IL-2 via calcineurin inhibition